Recent findings have indicated that the insulin-like growth factor type-2 receptor (IGF2R) shows frequent loss of heterozygosity and inactivation of the remaining allele in several common types of numan cancer (including breast cancer), suggesting that IGF2R is a tumor suppressor. Two main mechanisms have been proposed for the apparent tumor-suppressor activity of IGF2R: (1) decreasing the amounts of the growthpromoting, mitogenic peptide insulin-like growth factor II (IGFII), by targeting this factor to lysosomes for degradation; (2) increasing the activity of the growth-inhibitory transforming growth factor B (TGFB) by facilitating the conversion of this factor from the latent form into an active form. However, there is no direct experimental evidence that the IGF2R gene acts as a tumor suppressor. The aims of the present study are to examine in vivo the activity of IGF2R and to determine its ability to suppress mouse tumors induced by IGFII overexpression or mouse tumors sensitive to increased TGFB activity. To this end, we will produce Igf2r transgenic mice and will cross these mice with two existing transgenic lines whose tumors meet these criteria. First, we will cross Igf2r transgenic mice with Igf2 transgenic mice we have created, that develop frequent, multiple mammary carcinomas. We will compare the incidence of tumors in the Igf2r/Igf2 doubly transgenic and Igf2 transgenic females. This cross will test the hypothesis that increased IGF2R levels result in increased IGFII degradation and decreased incidence of tumors induced by IGFII. Second, we will cross Igf2r transgenic mice with TGFa transgenic mice, whose mammary tumors have been previously shown to be sensitive to increased TGFB dosage. We will compare tumor incidence between Igf2r/TGFa and TGFa transgenic females. This cross is based on the hypothesis that the tumor suppressor effects of IGF2R are due to its ability to assist in the conversion of TGFB from a latent into an active form. Third, we will examine the ability of the IGF2R to exert tumor suppressor effects when it is present in a mosaic state and expressed on cells other than those producing the tumor-inducing IGFII. The combined results from these experiments will help evaluate the effectiveness of IGF2R as a tumor suppressor and its potential usefulness for gene therapy of human tumors.